This K24 Midcareer Investigator Award application outlines a program of patient-oriented research involving the use of transcranial magnetic stimulation (TMS) in the study and modulation of brain plasticity during the acquisition of new skills and the recovery of function after a stroke. The principal investigator, Alvaro PascuaI-Leone, M.D., Ph.D., completed his neurology training in 1990 and a fellowship in human cortical physiology and motor control under the mentorship of Prof. Mark Hallett at the NINDS in 1994. He is an accomplished clinical investigator in the areas of motor learning and brain plasticity and has a proven track record as a mentor for graduate students, fellows, and junior faculty pursuing careers in behavioral neurology related clinical investigation. He has devoted much of his career to the development of TMS as a novel tool for the investigation of brain-behavior relations and a non-invasive method for modulation of cortical brain activity. Since 1999 he is an associate director of the Harvard-Thorndike General Clinical Research Center (GCRC). This application encompassess 6 broad specific aims that address: (1) the role of efferent demand and afferent input on human cortical plasticity in the normal adult; (2) the impact of focal brain injury on motor learning-related adult human cortical plasticity; (3) the modification of brain plasticity and motor learning in the setting of cortico-subcortical pathology; (4) the modulation of brain plasticity by mental imagery; (5) the modulation of brain plasticity by repetitive TMS; and (6) the mechanisms of action of TMS on the brain. Translational efforts combining insights from basic experiment on animal models, computer modelling, neurogenetics, neurohysiology, neuroimaging, cognitive neuroscience, and neurological studies are a cornerstone of these aims that provide different clearly defined paths for fellows and junior faculty to pursue patient-oriented clinical research under the guidance of clinical research and laboratory mentors. Regular meetings with Dr. PascuaI-Leone, multidisciplinary conferences, focused clinical rotations, participation in a clinical investigation course, continuing medical education courses on TMS, and a newly established mentorship program, co-directed by Dr. PascuaI-Leone, will round out the trainees experience. Taken together this work should provide novel insights into strategies to enhance recovery of function after brain injury and, at the same time, provide superb training for the next cadre of clinical investigators who will be counted on to extend this effort.